COMPRESSED MEDICAL GASES GUIDELINE
This guideline, issued under 21 CFR 10.90,
states principles and practices of general applicability that are not legal
requirements but are acceptable to the Food and Drug Administration (FDA). A
person may rely upon it with assurance of its acceptability to FDA or may
follow different procedures. Any person who chooses different procedures may,
but is not required to, discuss the matter in advance with FDA to preclude
expending money and effort on activity that FDA may later determine is
unacceptable.
This guideline
describes practices and procedures for compressed medical gas (CMG) fillers
(including companies engaged in home respiratory services) that constitute
acceptable means of complying with certain sections of the current good
manufacturing practice (CGMP) regulations for drug products (21 CFR Parts 210
and 211).
Previous editions of
this guideline were dated June 1981 and December 1983.
The guideline has been
revised to include the home respiratory segment of the industry. Also included
is an appendix containing questions and answers addressing various laws and
regulations as they pertain to the CMG industry. As in the previous editions,
the guideline states specific sections of the CGMP regulations followed by a
discussion of practices and procedures that FDA considers acceptable as a means
of meeting those requirements. Although all sections of the CGMP regulations
are applicable to CMG fillers unless specifically exempted, the guideline
addresses only those sections that prompted significant questions concerning
acceptable ways of compliance.
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Requirement
Section 211.63 requires that equipment used in the
manufacture, processing, packing, or holding of a drug product be of
appropriate design and suitably located to facilitate operations for its
intended use.
Guidance
One aspect of this requirement as related to the CMG
industry is that the equipment must be designed to assure that the proper gas
is put into the correct container. FDA considers acceptable elements of design
in this regard to include the following:
1. The CMG
manifolds used are dedicated to a single gas (e.g., oxygen). For mixtures of
two or more gases, the mixture is produced by filling the cylinders on
manifolds dedicated to mixtures (e.g., nitrogen/oxygen).
2. The
manifolds are equipped with fill connections that correspond only to the
container valve connection for that particular gas or mixture of gases so that
the wrong containers cannot be attached to the manifold. Other than for
laboratory functions, adapters should be used only when filling containers on
manifolds dedicated to the filling of mixtures. The use of manifold and
container valve connections recommended in the Compressed Gas Association (CGA)
pamphlet V-1 (ANSI B57.1; CSA-B96), Compressed Gas Cylinder Valve Outlet and
Inlet Connections is an acceptable system for this purpose.
3. Filling of
industrial and medical CMG containers (concurrently) on the same line is
acceptable, provided that the gas used for industrial purposes is equal to or
higher in quality than the medical gas and that containers have been prepared
in accordance with the "Testing and Approval or Rejection of Drug Product
Containers and Closures" and the "Drug Product Containers"
sections of this guideline.
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Requirements
Section 211.84(a)
requires that each lot of components be withheld from use until the lot has
been sampled, tested, or examined, as appropriate, and released for use.
Section 211.84(b)
requires that representative samples of each shipment of each lot be collected
for testing or examination.
Section 211.84(d)(1)
requires that at least one test be conducted to verify the identity of each
component.
Section 211.84(d)(2)
requires that each component be tested for conformity with all appropriate
written specifications for purity, strength, and quality. In lieu of doing the
testing itself, the manufacturer may accept a report of analysis from the
supplier of a component, provided the manufacturer (1) conducts at least one
specific identity test on the component, and (2) establishes the reliability of
the supplier's analyses through appropriate validation of the supplier's test
results at appropriate intervals.
Guidance
Questions have been
raised on how to meet the above types of testing requirements in situations
involving bulk deliveries of components that upon receipt are then commingled
in bulk storage tanks with other lots of the same component. For instance, it
may not be practical to sample a bulk liquefied gas directly from a tank truck
or from a bulk storage tank.
As an alternative to
actually sampling and performing all required testing on each shipment of the
component gas (i.e., either testing for all appropriate specifications or
receiving a report of analysis covering all such specifications and conducting
an identity test) before it is released and added to bulk storage tanks, the
following procedures may be used to achieve compliance with these requirements:
1. With a component
that will be put in the final container as a single gas, the sample is taken
either directly from the commingled lots in the bulk storage tank or indirectly
by sampling from the first container filled from the commingled lots in the
bulk storage tank after a new shipment has been added to the bulk tank. In the
latter instance, testing the first container filled serves both as a component
test and as a finished product test (as long as all appropriate tests are
performed).
2. With separate
components that will be used to produce a mixture of two or more gases, each
component is tested before the mixture is put into containers. Samples are
taken separately from the bulk storage tanks or from cylinders containing a
single component.
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Requirements
Section 211.160(b)
requires that laboratory controls include scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures designed to
assure that drug product containers and closures conform to appropriate
standards of identity, strength, quality, and purity.
Section 211.84(d)(3)
requires that containers and closures be tested for conformance with all
appropriate written procedures.
Guidance
Drug product
containers and closures for CMG's are typically reused numerous times. This
presents some special considerations regarding appropriate specifications and
testing for containers that customers return for refilling. Specifications and
testing procedures for CMG drug product container/closure systems should
include the following each time the container/closure system is refilled:
1.
Before refilling, an odor test of each CMG cylinder to detect foreign odors
(exceptions to this area are for anesthetic gases and carbon dioxide).
2.
A visual external inspection of each valve and container for dents, arc burns,
other damage, and oil or grease.
3.
For each aluminum cylinder, a visual check of the polyurethane coating or other
heat-sensitive indicator, if provided, for evidence of exposure to heat or
fire.
4.
For each steel CMG cylinder manufactured to specifications under Department of
Transportation (DOT) regulations (49 CFR Part 178), a dead ring test to
determine if the gas cylinder walls have been weakened by interior rust. (Dead
ring tests cannot be performed on cryogenic vessels, aluminum cylinders, or
clustered cylinders [e.g., cradles that require special periodic hydrostatic
testing].)
5.
For each CMG cylinder, a check to determine that the hydrostatic test is
conducted at the interval required by DOT regulations (49 CFR 173.34). The
testing intervals vary for different types of containers and gases. The DOT
regulations require that each cylinder be marked with the date of the last
hydrostatic test.
6.
A check to determine that each container is of the proper color to correspond
to any color-coding system employed, such as that recommended by the CGA in its
pamphlet C-9, Standard Color Marking of Compressed Gas Cylinders Intended for
Medical Use in the United States.
7.
A check of each cylinder or cryogenic vessel valve connection to determine that
it is the proper type for the particular type of CMG involved.
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Requirements
Section 211.94(c)
requires that drug product containers be clean.
Section 211.94(d)
requires that standards or specifications, methods of testing, and, where
indicated, methods of cleaning be written and followed for drug product
containers.
Guidance
One factor to consider
regarding the above requirements is the possible presence of foreign gas
residues in CMG cylinders before filling. An acceptable method of assuring that
cylinders do not contain foreign gas residues is to pull a vacuum on each
cylinder equal to 25 or more inches of mercury prior to filling with the CMG.
(Cryogenic vessels are seldom completely emptied and need not be evacuated
before filling.)
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Requirements
Section 211.125(c)
requires that procedures be used to reconcile the quantities of labeling
issued, used, and returned.
Section 211.130
requires there be written procedures designed and followed to assure that
correct labels, labeling, and packaging materials are used for drug products.
Guidance
CMG containers are not
always completely relabeled when they are refilled. For instance, a previous
container label may be left on when the container is refilled, and the label
need not be replaced unless it is outdated, damaged, or illegible. This
practice has resulted in some questions concerning appropriate labeling
controls and reconciliation procedures in such circumstances.
FDA considers it
acceptable to continue to use existing labeling on CMG containers that are
refilled if the procedures and controls provide for examining each container to
assure that the labeling completely conforms to the currently approved master
labeling and is otherwise suitable for continued use (i.e., it is undamaged,
legible, and does not bear previous lot numbers or expiration dates).
Acceptable procedures
for reconciling labeling in such circumstances would include recording (1) the
number of labels issued, (2) the number of containers actually relabeled and
(3) the number of labels destroyed and/or returned to inventory.
If a home respiratory
company (HRC) is distributing supplier filled cylinders only, and the HRC name
is on the label, the HRC must be identified as the distributor in compliance
with the labeling requirements of 21 CFR 201.1(h)(5).
If an HRC is
transfilling gas cylinders, the HRC becomes the manufacturer according to 21
CFR 201.1(b). If an HRC does not issue its own labels and if the HRC transfills
cylinders, the HRC's name and address must appear on the label as the filler or
transfiller.
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Requirements
Section 211.165(a)
requires that for each batch of drug product, there be appropriate laboratory
determination of satisfactory conformance to final specifications for the drug
product, including the identity and strength of each active ingredient, before
release.
Section 211.165(c)
requires that any sampling and testing plans be described in written procedures
that include the method of sampling and the number of units per batch to be
tested, and that the written procedure be followed.
Guidance
The following are
acceptable types of plans for sampling and testing CMG's before release in
certain types of filling operations. If nitrogen is a component of any mixture,
a test for identity of the nitrogen is not required. Identity is assured by the
filling procedure that introduces the nitrogen. If the filling procedure on the
manifold makes possible an alternate gas, an identity test to establish the
absence of that gas is to be performed.
1.
For a single CMG put into cylinders on a multi-cylinder manifold, at least one
cylinder of product from each manifold filling is tested for identity and
strength each time the cylinders are changed on the manifold.
2.
For a single CMG put into cylinders one at a time by individual filling
operations, at least one cylinder of product for each uninterrupted filling
operation cycle is tested for identity and strength. Examples of an
uninterrupted filling operation cycle are one day's or one shift's production
using the same personnel, equipment, and lot or commingled lots of component.
3.
For a finished CMG produced by combining two different gases in a cylinder,
every cylinder is tested for the identity and strength of one of the gases, and
at least one cylinder from each manifold filling is tested for identity of the
other gas in the mixture.
4.
For a finished CMG produced by combining three different gases in a cylinder,
every cylinder is tested for the identity and strength of two of the gases and
at least one cylinder from each manifold filling is tested for the identity of
the third gas in the mixture.
5.
For liquefied gas put into cryogenic home units at the plant for delivery to
users, each home unit is tested for identity and strength.
6.
Home units that are retained by customers and are serviced in place
periodically by refilling from vehicle mounted vessels need not be directly
tested after filling if the filling firm has available suitable records of
analysis covering the identity and strength testing performed on a sample taken
from its vehicle mounted vessel, or has satisfied the conditions in 8 below.
7.
Each filled CMG cylinder is tested for leaks using an appropriate method, such
as a leak detection solution applied to the valve area.
8.
For HRC firms dispensing liquid oxygen from vehicle mounted vessels, acceptable
means of compliance with the identity and strength testing requirements are as
follows:
a.
If the HRC obtains bulk liquid oxygen from a bulk supplier, the identity and
strength test is performed by the bulk supplier and witnessed by the HRC.
Documentation of this testing is maintained by the HRC.
b.
If the HRC obtains bulk liquid oxygen from a bulk supplier who supplies a
certificate of analysis but the test is not witnessed by the HRC, the HRC must
perform an identity test on each lot received and establishes the reliability
of the supplier's analyses at appropriate intervals.
c.
If the HRC neither witnesses the identity and strength test nor receives a
certificate of analysis, the HRC must test each vehicle mounted vessel filled
by the bulk supplier for identity and strength.
9.
If the HRC owns or leases a stand tank (stationary holding tank), the HRC must
perform a test for identity and strength taken directly from the stand tank
after each oxygen delivery before any vehicle mounted vessel is filled. Vehicle
mounted vessels filled from this stand tank need not be tested if the HRC can
demonstrate compliance with all of the following conditions:
(1)
No other stand tanks are located at the facility;
(2)
The vehicle mounted vessels filled from the stand tank are dedicated to the
delivery of oxygen by the HRC for home care use only; and
(3)
The vehicle mounted vessels filled from the stand tank have not been completely
emptied or have not been out of service.
---
Requirement
Section 211.184(c)
requires that records include an individual inventory record of each component,
a reconciliation of the use of each lot of the component, and sufficient
information to allow determination of which batches or lots of drug product are
associated with the use of each component.
Guidance
The agency recognizes
that accurate component inventory records, including reconciliation of the use
of each lot, are difficult to maintain for bulk liquefied gases. Complications
include normal loss of the gas through vaporization, which may amount to l0
percent or more, and the commingling of component lots in bulk storage tanks.
FDA does not expect in
such circumstances that the reconciliation will allow 100 percent
accountability. The procedures for reconciling the use of components can allow
for normal storage and operating losses as long as the procedures require
further investigation in the event of unexplained discrepancies such as losses
beyond established normal levels.
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Requirement
Section 211.188
requires that batch production and control records be prepared for each batch
of drug product produced and include complete information relating to the
production and control of each batch. These records must include:
(a)
An accurate reproduction of the appropriate master production or control
record, checked for accuracy, dated, and signed; and
(b)
Documentation that each significant step in the manufacture, processing,
packing, or holding of the batch was accomplished, including all particular
information specified in this section.
Guidance
Questions have been
raised on whether batch production and control records, which in the CMG
industry are frequently in the form of a pumper's or filler's log, must contain
a complete copy of all corresponding master production and control information.
It is acceptable for
the batch production and control records to incorporate detailed production and
control information by reference as long as significant processing steps are
included in the batch records. As one example, it is suitable for the batch
production and control record to provide an instruction such as "Evacuate
cylinders per Standard Operating Procedure XYZ," if the details of
Standard Operating Procedure XYZ appear in the master production and control
records.
The requirement for
supervising review of the batch production control records may be satisfied if
the person in charge reviews these records daily and this review is noted on
the records.
---
Requirement
Section 211.194(a)(2)
requires that laboratory records include a statement of each method used to
test the sample, indicating
the location of data
establishing that the methods meet proper standards of accuracy and reliability
for the product tested. If the method used is in a recognized standard
reference, such as the current United States Pharmacopeia/National Formulary,
and is not modified, a statement of the method and reference will suffice.
Guidance
Several CMG's, being
recognized in the United States Pharmacopeia/National Formulary, must meet the
requirements contained in the official compendium. This does not mean, however,
that the official tests must necessarily be used in testing for batch release
purpose. Alternative methods may be used to demonstrate satisfactory
conformance with the appropriate requirements, but if a nonofficial test method
is used for an official article, the laboratory records must document that the
method used is equal to or superior to the compendial method in terms of
accuracy and reliability.
For purposes of this guideline, the following
definitions apply:
1. Compressed medical
gas (CMG)--Any liquefied or vaporized gas alone or in combination with other
gases which is a drug as defined by Section 201(g)(1) of the Federal Food, Drug,
and Cosmetic Act (the Act) (21 U.S.C. 321(g)(1)). NOTE: Calibration gases and
lung diffusion mixtures are classed as devices (2l CFR 868.6400).
2. Container--A metal
container designed to contain either liquefied or vaporized CMG.
3. Cryogenic vessel--A
metal container designed to contain liquefied CMG at extremely low
temperatures.
4. Cylinder--A metal
container designed to contain CMG at a high pressure.
5. Dead ring
test--Also called the "hammer test." A test used to determine the
soundness of a cylinder by striking the side of the cylinder. If a clear
bell-like sound results, the cylinder is considered satisfactory. If a dull
sound results, the cylinder is not considered suitable for filling with a high
pressure CMG (not applicable to aluminum cylinders).
6. Home Respiratory
Company (HRC)--Any firm that fills, transfills, or distributes compressed
medical gases intended for use by patients at their residence.
7. Manifold--Equipment
or apparatus designed to fill one or more CMG containers at a time.
8. Odor test--A test
performed by opening a CMG cylinder valve to allow the CMG to flow into a
cupped hand. The gas is then organoleptically examined by smelling for foreign
gases. This test is not done on cylinders containing anesthetic gases or carbon
dioxide.
CURRENT GOOD MANUFACTURING PRACTICE
QUESTIONS AND ANSWERS
ON COMPRESSED MEDICAL GASES
1. QUESTION: Why are
compressed medical gases for medical use considered prescription drugs?
ANSWER: Because their
use as drugs, without the supervision of a licensed practitioner or by properly
instructed emergency personnel, is not safe.
2. QUESTION: Are CMG
liquefaction plants and container filling facilities required to register with
FDA as drug manufacturers?
ANSWER: Yes, a drug
registration form must be submitted to FDA for every liquefaction plant and for
every container filling facility. Furthermore, a drug listing form must be
submitted to FDA listing each compressed medical gas filled or relabeled at
that facility. Drug registration and drug listing forms can be obtained from
any FDA District Office (see attached list).
3. QUESTION: How often
are such plants inspected by FDA?
ANSWER: The Act
requires FDA to inspect each liquefaction plant and each container filling
facility at least once every two years. However, more frequent inspections may
be made for several reasons; such as to investigate an industry or consumer
complaint, product recall, or as a follow-up to a Warning Letter.
4. QUESTION: What are
FDA investigators authorized to inspect?
ANSWER: FDA
investigators are authorized to enter a drug manufacturer's place of business
to inspect the buildings, equipment, finished and unfinished materials,
containers, and labeling. In the case of prescription drugs such as compressed
medical gases, the inspection authority includes access to all records
(including shipping and receiving records), but not including financial
records.
5. QUESTION: What do
FDA investigators routinely look for during an inspection?
ANSWER: They look to
see whether compressed medical gases are being manufactured according to FDA's
current good manufacturing practice (CGMP) regulations. FDA investigators will
also look at labeling to determine compliance with FDA's labeling regulations
(21 CFR Part 201).
6. QUESTION: What are
the CGMP regulations?
ANSWER: Section
501(a)(2)(B) of the Act requires that the methods used in the manufacture,
processing, packing, or holding and the facilities used must conform to current
good manufacturing practice. The CGMP regulations explain to drug manufacturers
what controls they must have in order to comply with the Act and, thereby,
assure that the drug products they produce meet the quality and purity
characteristics that they are represented to have. These regulations are
published in Title 21, Parts 210 and 211 of the Code of Federal Regulations,
and are included in the volume containing Parts 200 to 299. Copies of that
volume may be ordered from:
Superintendent
of Documents
Government Printing Office
Washington, D. C. 20402
Government Printing Office
Washington, D. C. 20402
7. QUESTION: What are the most common
violations that FDA investigators look for?
ANSWER: The most
common violations are:
a) Failure to
establish written operating procedures [21 CFR 211.100(a)];
b) Failure to follow
the written operating procedures [21 CFR 211.100(b)];
c) Failure to test the
final product for identity and strength [21 CFR 211.165];
d) Failure to keep
adequate batch production and laboratory records [21 CFR 211.188 &
211.194]; and
e) Failure to register
as a drug manufacturer.
8. QUESTION: What must
a batch record contain?
ANSWER: A batch record
(pumper's log) must include documentation that each significant step in the
manufacture, processing, packing, or holding of the batch has been
accomplished. It must also include the identity of the person(s) performing and
directly supervising each significant step. [21 CFR 211.188]
9. QUESTION: Must a
firm produce a batch record for each batch of CMG filled and how long must it
be retained?
ANSWER: The firm must
produce a batch record (pumper's log) for every batch of CMG filled. This batch
record and all other production and control records must be retained on file by
the firm for at least one year after the expiration date of the batch. [21 CFR
211.180]
10.QUESTION: What if
the person performing the significant step, such as vacuum evacuation of the
cylinders, fails to indicate that the step was accomplished?
ANSWER: The supervisor
or person checking the batch record should determine if the step was
accomplished and, if it was, require completion of the batch record. If the
record review by FDA reveals that the batch record is incomplete, FDA assumes
that the step was not accomplished.
11.QUESTION: What
should a firm do if a mix-up is discovered?
ANSWER: The batch
should be rejected, blown down, and evacuated per written procedures. An
investigation should be initiated to determine the cause of the mix-up. If the
lot has been distributed the firm should initiate an immediate recall and
notify the nearest FDA district office (see attached list).
12.QUESTION: How soon
will the firm be notified of the FDA investigator's inspectional findings?
ANSWER: Prior to
finishing the inspection, the FDA investigator will discuss the findings of the
inspection with the most responsible person present. A Notice of Observations
(Form FDA-483) will be prepared by the investigator listing the conditions
which the investigator considers to be objectionable. If the items listed are
serious deficiencies, the firm may also receive a Warning Letter from FDA's
District Office.
13.QUESTION: What
court-enforced actions can be taken against a firm that violates the Act?
ANSWER: The
court-enforced actions include seizure of finished product, bulk product,
ingredients, and equipment; temporary or permanent injunction from
manufacturing or filling CMG's; and criminal prosecution.
14.QUESTION: What are
the penalties for violating the Act?
ANSWER: If found guilty
of violating a provision of the Act, an officer or employee of the firm may be
imprisoned for up to one year and/or fined up to $100,000 ($250,000 if death
occurs) for each violation. If the prohibited act was committed with intent to
defraud or mislead or if an officer or employee is convicted a second time
under the Act, the offense is punishable by a fine of $250,000 to $500,000 and
imprisonment of up to three years for each violation. The firm can also be
fined the same amounts. (Note: The limits of the amount of fine that can be
imposed were raised by the Comprehensive Crime Control Act of 1984, for all
criminal violations for which the basic Federal law imposes a prison sentence
of six months or more.)
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Date created: March 10, 1997; last update: July 6, 2005